REQUISITOS ECONÓMICOS
TRIBUNAL ELECTORAL DEL PODER JUDICIAL DE LA FEDERACIÓN PRESUPUESTO BASE UCOC
This interim analysis of the larger TICOPA RCT provides insight into the outcomes seen in multiple domains of early PsA. A high proportion of patients achieve the MDA state within the 48 week study period and good responses are seen in all domains of disease and in PROMs. Further validation of the MDA criteria is provided by their concurrent validity with the ACR outcome measures as seen in previous validation work. Due to the small size of the sample, it is not possible, at this stage, to properly investigated predictors of response. However in future this should be possible with the full TICOPA dataset.
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Conclusions and Future Directions
This thesis is concerned with developing clinical tools and methodology to improve the outcome of PsA. This final chapter will present an overview of the results of the thesis, looking at all of the studies performed and analysing the findings in the context of current literature. The potential research questions arising from the work in this thesis will then be considered.
PsA is now recognised as a potentially damaging and destructive disease and the aim of this research was to provide tools to improve disease management and optimise outcome. The first priority is to identify patients early in the course of their disease so that assessment and therapy can be initiated. However it was identified that there was a lack of validated classification criteria to aid identification of patients with early PsA for both clinical interventions and future research. The recently developed CASPAR criteria have both high sensitivity and specificity in established disease (Taylor et al. 2006), but it is stated in the paper that less than 5% of the original study population had a disease duration of less than 12 months. A few small studies have suggested that the CASPAR criteria may be useful in early disease but no properly powered studies have addressed their validity in early PsA.
Once identified, the next challenge was to optimise management for patients with early PsA. In RA, management has focused on early intervention in the course of disease with “tight control” of inflammatory disease to improve prognosis. However, this concept of “tight control” has not been investigated in PsA. In the RA studies, validated outcome measures such as DAS, clinical disease activity index (CDAI) and simplified disease activity index (SDAI) give definitions of low disease activity or remission that can be used as a target for therapy. One of the major issues preventing research in this area, perhaps reflecting a lack of research in PsA, was the lack of validated criteria to define an “acceptable” disease state. The concept of minimal disease activity had been defined by OMERACT but validated criteria had only been developed for RA using this framework.
This thesis therefore concentrated on these two major challenges to the optimal management of early PsA, and aimed to provide feasible clinical solutions to the early identification of PsA and management using optimal treatment targets.
Chapter Three The validity of the CASPAR criteria in early PsA
In Chapter Three, the CASPAR criteria were found to be sensitive and specific in identifying early PsA. Although their sensitivity is slightly lower than that found
in established disease, they performed better than the previous gold standard classification criteria developed by Moll & Wright. Detailed assessment of the patients and controls included in this study highlighted some of the clinical phenotypical differences between early PsA and other form of early inflammatory arthritis. However, there were no individual features that could be relied upon to differentiate diagnosis between PsA and other forms of inflammatory arthritis. Chapter Four Imaging in early PsA – the extent of sub-clinical disease
Modern imaging is more sensitive than clinical examination for detecting a variety of important joint pathologies. A detailed assessment of a sub-group of patients with early PsA investigated the US evidence for arthritis and enthesitis. There were low levels of sub-clinical arthritis and particularly low levels of US- identified enthesitis. Similarly, the correlation between clinical and US assessment was high suggesting that, in most cases of early PsA, clinical examination provides a reasonable assessment of disease activity for both synovitis and enthesitis.
Chapter Five Defining MDA in PsA
MDA criteria were developed for use in PsA using a web-based questionnaire of international experts. The criteria include clinical measures of arthritis, enthesitis, skin disease and PROMs to ensure that all aspects of psoriatic disease are encompassed.
Chapter Six Validation of the MDA criteria for PsA
Following on from the development of the MDA criteria in the previous chapter, validation work was completed following the methodology of the OMERACT filter. This analysis provided evidence within the domains of truth, discrimination and feasibility proving the performance metrics of the PsA MDA criteria. A large observational cohort and two large datasets from interventional randomised controlled trials were utilised in order to assess their validity in routine clinical practice and as a potential outcome measure for future interventional trials. Chapter Seven Tight Control of PsA – preliminary analysis of a large RCT
The TICOPA study is the first prospective study to utilise the MDA criteria as a target for treatment in an intensive treatment regime. The study is ongoing and therefore data are limited within this thesis chapter. The preliminary analysis identified significant clinical improvements seen with treatment of early PsA in all domains of the disease. It also confirmed the concurrent validity of the MDA criteria with significant agreement seen between these and other composite outcome measures used in PsA that were designed to measure similar constructs.
In summary, the work in this thesis provides a sensitive and specific tool for early identification of PsA patients and a validated target for treatment that can be utilised in clinical practice, while also presenting preliminary data from a study of a tight-control treatment regimen.
Discussion and limitations of current work
Research addressing the use of the CASPAR criteria in early disease in Chapter Three provides evidence for their use as classification criteria in early disease. Early diagnosis of PsA is recognised to be difficult due to the heterogeneity in clinical phenotype, the potential for patients to present “sine psoriasis” and the lack of confirmatory blood tests. Prior studies developing and validating the CASPAR criteria have concentrated on established disease. The few studies addressing their use in short duration disease have only included a small number of patients and the majority have lacked controls, meaning that only sensitivity and not specificity can be calculated. The sensitivity for the CASPAR criteria was found to be slightly lower in early disease than that in established PsA. Previous authors have predicted this finding as there is little chance of patients fulfilling the radiological element of the CASPAR criteria at an early stage in disease (D'Angelo et al. 2009). However, the criteria do have better sensitivity than the Moll and Wright criteria as they allow a diagnosis of PsA without a requirement to have both arthritis and current evidence of psoriasis. The use of other typical features of PsA to make a diagnosis using the CASPAR criteria means that these criteria are more inclusive when classifying PsA.
The main limitation of the work in Chapter Three is that it does not address the need for diagnostic criteria in an unselected early arthritis population. The ideal characteristics for such criteria are defined according to their planned use. Classification is a separate issue to clinical diagnosis, although following the publication of classification criteria, clinicians frequently misuse them for diagnosis. Classification criteria, used in research, should have a greater emphasis on specificity to ensure a homogeneous population for therapeutic trials and laboratory and genetic studies. Diagnostic criteria should be designed with a higher sensitivity to ‘screen’ for a particular disease. In diagnosis the impact of misclassification for an individual may have a great impact on their future care and is therefore significant. However in classification, the criteria are applied to a group recruited for research where misclassification of one individual will have less impact.
There are therefore two issues which prevent the work in Chapter Three from addressing this need for diagnostic criteria. Firstly, the CASPAR criteria were developed as classification criteria rather than diagnostic criteria and have also been tested as such in this cohort. The high specificity found in this study means that the
criteria are ideal for the classification of patients for future clinical trials. However, their lower sensitivity means that their use as diagnostic criteria is limited.
Secondly the selection of patients used to test the criteria creates limitations. Patients were assigned to either the case or control cohort if the consultant felt they had a diagnosis of PsA or an alternative inflammatory arthritis. Therefore there will have been some patients excluded from the recruitment where the diagnosis was more uncertain. This results in a higher sensitivity and specificity when testing the criteria in this cohort, compared to their true validity in a mixed undifferentiated arthritis population.
The development, subsequent validation and prospective routine use of the MDA criteria has provided a tool for future research and clinical assessment of PsA patients. There is evidence provided in Chapter Four that clinical assessment shows good correlation with US for both arthritis and enthesitis activity suggesting that clinical assessment is reliable in PsA. The concept of MDA was developed by OMERACT, firstly in the field of RA (Wells et al. 2005), and has now been utilised in other forms of arthritis (Magni-Manzoni et al. 2008). The conceptual definition was agreed by a large international group of experts within the OMERACT framework. The development of the MDA criteria for PsA was done with the assistance and expertise of the GRAPPA steering committee and wider membership. The criteria are based on “paper cases” of real clinical patients and were created using expert consensus of a worldwide sample of rheumatology and dermatology experts in psoriasis and PsA.
In Chapter Six the validity of the MDA criteria was tested in both observational cohorts and interventional trial datasets. Using both of these settings allows evaluation of multiple aspects of the OMERACT filter and provides evidence of their utility both as an outcome measure for future research and as a tool for clinical practice. Importantly, their prognostic ability was identified in both cohorts providing encouraging evidence that treating to an objective target can impact on long term outcome. Some aspects of the OMERACT filter have not been assessed or could benefit from further work. The assessment of criterion validity is not possible as there is no recognised gold standard. In these situations, concurrent validity is assessed as an alternative. However this is also difficult as it requires comparing the MDA criteria against other criteria measuring similar constructs. The level of agreement between certain response criteria (such as the ACR measures) and other measures of disease activity has been assessed in the IMPACT data in Chapter Six as well as in the preliminary analysis of the TICOPA data in Chapter Seven. However, at present, there are few composite disease activity measures that encompass all aspects of psoriatic disease and these are still in development.